Several classes of immunoglobulin(s) [hereinafter referred to as Ig(s)] are well known as antibodies concerned with immune response. Most of Igs, especially immunoglobulin G (hereinafter referred to as IgG) which is one class of Igs, play an important role in self-defense mechanisms in mammals against foreign substances such as viruses, bacteria, tumours and the like.
However, immunoglobulin E (hereinafter referred to as IgE) which is another class of Igs, has been confirmed to be primarily responsible for diseases such as allergic bronchial asthma, allergic rhinitis, atopic dermatitis, hypersensitiveness, and the like (Journal of Immunology, Vol. 10, p 445. 1925, Journal of Immunology, Vol. 97, p 75, 1966). It has also been confirmed that serum concentrations of IgE in most allergic patients suffering from those diseases are higher in general than those in normal ones.
Therefore, selective inhibition of its formation might be an effective pharmacological approach for the treatment of allergy in the human. Attempts have been widely made to develop the selecive inhibitors of IgE formation. The prospective inhibitors preferably would not inhibit excessively any class of Igs except IgE for reasons mentioned above.
Up to the present time, various compounds have been reported to inhibit IgE formation in literature such as Japanese Patent Application (OPI) No. 76/87 (the term "OPI" used herein refers to an unexamined Japanese patent application); U.S. Pat. Nos. 4,395,405 and 4,691,018; British Patent Application No. 2,020,665(A) and J. Med. Chem. Vol. 25, No. 12, pages 1495-1499, 1982.
Of particular interest with respect to the present invention are publications which disclose compounds having a substituted 4H-quinolizin-4-one nucleus.
Process embodiment for production of 1-, 2- and 3-substituted 4H-quinolizin-4-one derivatives are described in Yakugaku Zasshi, Vol. 89, No. 2, pages 203-208, 1969, ibid. Vol. 90, No. 2, pages 127-131, 1970, ibid. Vol. 91, No. 12, pages 1275-1278, 1971, ibid. Vol. 94, No. 1, pages 44-49, 1974, Chem. Pharm. Bull, Vol. 18, No. 1, pages 124-127, 1970, ibid. Vol. 21, No. 5, pages 921-925, 1973, J. Heterocycl. Chem., Vol. 10, No. 2, pages 139-142, 1973, J. Chem. Soc. (c), pages 1143-1146, 1969, Monatish. Chem., Vol. 114, pages 485-493, 1983.
Anti-tumor activity of 1-, 2- and 3-substituted 4H-quinolizin-4-one derivatives of formula: ##STR1## where R is methylthio, piperidino, N,N-diethyl aminoethylamino and benzylamino is disclosed in Yakugaku Zasshi, Vol 97, No. 9, pages 1039-1045, 1977.
European Patent Application No. 157346(A2) and Japanese Patent Application (OPI) No. 222482/85 which are counterparts of British Patent Application Nos. 8408292 and 8429710, filed March 30, 1984 and November 23, 1984, respectively, disclose quinolizinone derivatives having an inhibitory activity on allergies and ulcers, which derivatives correspond to the formula: ##STR2## where R.sup.1 is carboxy, amidated carboxy, cyano, thiocarbamoyl or tetrazolyl; R.sup.7 is hydrogen or aryl; R.sup.2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; R.sup.3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy, aryl which may have suitable substituents, arylthio, aroyl, ar(lower)alkyl, arenesulfonyl, arylamino which may have a suitable substituent or aryloxy; and R.sup.2 and R.sup.3 can be located at any place on the quinolizine ring and can be linked together to form -CH.sub.2 CH.sub.2 CH.sub.2 -, -CH=CH- or -CH=CH-CH=CH-; and pharmaceutically acceptable salts thereof.
Japanese Patent Application (OPI) No. 77385/87 which is a counterpart of U.S. patent application Ser. No. 770,953 filed August 30, 1985, U.S. Pat. No. 4,698,349 discloses quinolizinone derivatives having an inhibitory activity on allergies and ulcers, which derivatives correspond to the formula: ##STR3## where R.sup.1 is carboxy, tetrazolylcarbamoyl or amino-substituted triazolylcarbamoyl; R.sup.2 is hydrogen or lower alkoxy; R.sup.3 is hydrogen, aroyl, aryl, carboxy or protected carboxy; R.sup.4 is hydrogen or hydroxy; with the proviso that (i) when R.sup.3 is hydrogen, R.sup.4 is hydroxy, (ii) when R.sup.3 is aryl, R.sup.1 is amino-substituted triazolylcarbamoyl and (iii) when R.sup.3 is aroyl, R.sup.2 is lower alkoxy; and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,650,804 which is a counterpart of British Patent Application Nos. 8408292 and 8429710, filed March 30, 1984 and November 23, 1984, respectively, disclose quinolizinone derivatives having an inhibitory activity on allergies and ulcers, which derivatives correspond to the formula: ##STR4## where R.sup.1 is tetrazolylcarbamoyl; R.sup.7 is hydrogen or aryl selected from phenyl, tolyl, xylyl, cumenyl, naphthyl and biphenylyl; R.sup.2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; R.sup.3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy, phenyl, naphthyl, biphenylyl, phenyl having one or more substituents selected from halogen, lower alkyl and lower alkoxy, arylthio selected from phenylthio, tolylthio, xylylthio, cumenylthio, naphthylthio and biphenylylthio, aroyl selected from benzoyl, toluoyl and naphthoyl, ar(lower)alkyl selected from phenyl(lower)alkyl, tolyl(lower)alkyl, xylyl(lower)alkyl, cumenyl(lower)alkyl, naphthyl(lower)alkyl and biphenylyl(lower)alkyl, arenesulfonyl selected from benzenesulfonyl and p-toluenesulfonyl, arylamino selected from phenylamino, naphthylamino, biphenylylamino, phenylamino having lower alkyl on the nitrogen atom or aryloxy selected from phenoxy and tolyloxy; or pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,698,349 filed August 30, 1985, disclose quinolizinone derivatives having an inhibitory activity on allergies and ulcers, which derivatives correspond to the formula: ##STR5## where R.sup.1 is carboxy, carbamoyl, phenylcarbamoyl which may have hydroxy, cyano or thiocarbamoyl; R.sup.7 is hydrogen or aryl selected from phenyl, tolyl, xylyl, cumenyl, naphthyl and biphenylyl; R.sup.2 is hydrogen, hydroxy, lower alkyl or lower alkoxy; R.sup.3 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyloxy, phenyl, naphthyl, biphenylyl, phenyl having one or more substituents selected from halogen, lower alkyl and lower alkoxy, arylthio selected from phenylthio, tolylthio, xylylthio, cumenylthio, naphthylthio and biphenylylthio, aroyl selected from benzoyl, toluoyl and naphthoyl, ar(lower)alkyl selected from phenyl(lower)alkyl, tolyl(lower)alkyl, xylyl(lower)alkyl, cumenyl(lower)alkyl, naphthyl(lower)alkyl and biphenylyl(lower)alkyl, arenesulfonyl selected from benzenesulfonyl and p-toluenesulfonyl, arylamino selected from phenylamino, naphthylamino, biphenylylamino, phenylamino having lower alkyl on the nitrogen atom or aryloxy selected from phenoxy and tolyloxy; or pharmaceutically acceptable salts thereof.
In none of the publications described above there is any disclosure or suggestion that novel substituted 4H-quinolizin-4-one of the type provided with the present invention might exhibit an inhibitory activity against IgE formation in mammals.